4, 7-diamino-n-(substituted)-2-alkylthio-6-pteridinecarboxamides



3,177,217 I 4,7-DIAMINO-N-(SUBSTITUTED)-2-ALKYLTHIO-6-PTERIDINECARBOXAMIDES Thomas S. Osdene, West Chester, Pa., assignor toAmerican Home Products Corporation, New York, N.Y., a

corporation of Delaware No Drawing. Filed Dec'. 3, 1962, Ser. No.241,487

3 Claims. (Cl. 260-2515) This invention is concerned with novel6-pteridinecarboxamides having significant antiviral activity and withprocesses for making the same.

The compounds sought to be patented have valuable therapeuticapplications and can be represented by the following general formula:

i IcoNAY lk -L NH A S N N a I wherein AlkS represents a lower alkylthioradical having from 1 to 4 carbon atoms; R is hydrogen or alkyl; A is astraight chain or branched alkylene radical having 2 to 5 carbon atoms;Y is a di-lower alkylamino, a morpholinyl, piperidinyl, piperaz inyl, orpyrrolidinyl radical.

The novel compounds of the present invention are prepared by the processgenerally illustrated by the following equation:

In the above formulas, Al kS, R, A, and Y have the same meaningpreviously set forth.

In practising the process outlined above, the com,- pounds of thisinvention are prepared by heating under autogenous pressure in ananhydrous neutral polar solvent in the presence of a catalytic amount ofan alkaline condensation agent approximately equimolar amounts of a4,6diamino2-alkylth-ioe5-nitrosopyrirnidine (II) and a 2-cyano-N-(substituted)acetamide (III). This reaction is carried out at atemperature Within the range of about 60 -to 200 C. but preferably at ornear the boiling point of the reaction mixture. Neutral polar solventssuitable in the reaction of interest include methanol, propanol,ethanol, butano'l, glycol ethers such as Z-methoxy ethanol, 2- ethoxyethanol methoxy and ethoxy propanols as well as amides such asdimethylformarnide, diethylforrnamide and dimethyl acetamide. Agentssuitable for promoting the instant reaction include the alkali metals,their alkoxides and their alkoxyalkoxides. Preferred among thesecatalysts are sodium metal, sodium methoxide, potassium ethoxide andsodium a-ethoxy ethoxide.

3 ,1 7 'Z ,Z l 7 Patented Apr. 6;, 1965 r' l l ICC When preparing the4,7-diamino-N-(dialkylaminoalkyl)-2-alkylthio-6-pteridinecarboxarnidesaccording to the process of the invention, by heating a4,6-di-amino-2-alkylthio-S-nitrosopyrimidine and the appropriate 2cyanoN- (subs-tituted)acetamide, it should'be noted that a precipitateforms after a short period of boiling. After cooling the reaction massto room temperature, the precipitate is filtered off and dried. Thismaterial is extracted with absolute ethanol and the crude productprecipitates upon cooling the alcohol extract.

All the products of this invention canbe purified by dissolving them ina lower alkanol solvent such as ethanol or 2-ethoxyethanol.

The following examples, in which all temperatures are given in degreescentigrade, illustrate the best mode of practising the invention.

Example 1 To a solution of 0.2 g. of sodium metal in 500 ml. of absoluteethanol was added 9.25 g. of 4,6-diamino-2-methylmercapto-S-nitrosopyrimidine and the mixture was stirredmechanically and brought to the boil. To the mixture was added 10.83 g.of 2-cyano-N-(3-diethylarninopropy1)-acetam-ide and the whole was boiledunder reflux for 10 mins. during which time a precipitate was deposited.After cooling, the precipitate was removed by filtration and dried,wt.=l0.8, M.P'. 307 (effervescent). This material "was placed into aSoxhlet extractor and was extracted with absolute ethanol. A crystallinesubstance was obtained on cooling of the alcoholic extract. Furtherrecrystallization of the solid from 2-ethoxyethan0l afforded 4,7 diaminoN-(3-diethylaminop-ropyl)-2- methylmercapto-6-pteridinecarboxamide, M.P.305 C.

Analysis.Calc.: (3:49.43, H=6.64, N=30.75, S: 8.79. Found: 0:49.47,H=6.49, N=30.72, S=8.50.

Example 2 4,7-diaminoN-(Z-dimethylarninoethyl)-2-methylmercapto-6-pteridinecarboxamide isprepared from 7.6 g. of Z-cyano-N-(2-dimethylaminoethyl) acetamide and9.25 g. of 4,6-diamino-Z-methylmercapto-5-nitrosopyrimidine followingthe procedure of Example 1.

Example 3 4,7 diamino-N-(2-diethylaminoethy1) 2methylmercapto-6-pteridinecarboxamide is prepared from 9.1 g. of2-cyano-N-(Z-dicthylaminoethyl) acetamide and 9.25 g. of4,6-diamino-Z-methylmercapto-S-nitrosopyrirnidine following theprocedure of Example 1.

Example 4 4,7 diamino -'N(3-dimethylaminopropyl)-2-rnethylmercapto-6-ptericlinecarb1oxamide isprepared from 8.4 g. of 2-cyano-N-(S-dimethylaminopropyl) acetamide and9.25 g. of 4,6-diamino-Z-methylnrercapto-5-nitrosopyrimidine followingthe procedure of Example 1.

Example 5 Starting Compounds Products 4,6-diamino-Z-ethylmereapto-S-nitrosopyrimidine and Z-cyano- N-(2-di-isopropylaminoethyl) aeetamide;4,6-diamino-2-propylmereapto-S- nitrosopyrimidine and 2-cyano4,6-diomino-2-inethyhneteapto-5- nitrbsopyrimidine and 2-cyano iN-(Z-piperidinoethyl) acetamide.

4,6-diamiuo-2-methylmercapto-5- nitrosopyrimidine and 2-cynno-N-(Zpyrrolidinoethyl) acetamide. V

4,6-diamino-2-methylrnercapto 5-nitrosopyrimidine and 2-cyano-N-(3-morpholinopr0pyl) acetamide.

4,6-diamino-2-methy1metcapto-5-.

nittosopyrimidine and Z-eyano- 'N(3-piperidinoethyl) acetamide.

4,7-dia-min-N-(Z-di-isopropylaminoethyl)-2-ethy1-mercapto- G-pteridinecarboxamide.

4L7-diamin0-N-(3-di-n butyI aminopropyl) -2-p r0py1mercapto-G-pteridineoarboxamide.

4,7-diamino-N-(bdin1ethyl aminobutyl)-2-propyhnereapto-6- Ypteridinecarboxamide.

4,7-diamino-N- (2-dimethylaminopropyl)-2-methy1mercapto-6-pteridinecarboxemide.

4,7-dia mino-N-(2-morpholino ethyl) -2-meth'ylmerca'pto-6pteridineearboxamlde 47-dia mino-N-(-3-morpholinopropyl)-2-methylmercapto-6-' pteridineearboxamide.

4,7-diamin0-N-(3-piperidinopropyl)-2-methy1mercapto-6-pteridinecarboxamide. i.

The compounds of this invention show antiviral activity and'areparticularly useful-in treating hepatitis in mam mals. a

i What is claimed is: V r 5 l. Acornpound f the'formula: a I 1 a V N V vAllrS-k N I I I whereiuAlkS representsa lowefalkylthio radical; R isselected from the group consisting of hydrogen and lower alkyl; A is anunsubstituted alkyleneradical having from 2 to '5. carbon 'atoms'in thechaim and Y is selected from the group consisting of di-loweralkylainino, morpholino, .piperidino and pyrroliclino; V

2. 4,7-diamino-N-(diloweralkylamiuoethyl). 2 loweralkylthio6-pteridineearboxamide. V

mercaptol-6-pteridineearb oxamide.

2,963,478 (12/60, Weinstock :260-251i Examiners.

3. 4,7-diamino-N-(2 diethylaminoethyll 2 --methyl- 7

1. A COMPOUN OF THE FORMULA: